Flavivirus-Host Molecular Interactions  


  HEADDr. Philippe DESPRES / pdespres@pasteur.fr
  MEMBERSDr. Matthieu BLANCHET / Jean-Baptiste BRAULT / Anne-Claire BREHIN / Dr. Lark COFFEY / Marie-Pascale FRENKIEL/ Dr Marc GRANDADAM/ Eva MERTENS / Brigitte MILLIOT / Isabelle MOLTINI / Dr. Nathalie PARDIGON / Dr Charlotte RENAUDAT


  Annual Report

Flavivirus-Host Molecular Interactions laboratory is dedicated to the understanding of molecular basis of pathogenicity of most important mosquito-borne RNA viruses (arboviruses) in medical field such as flaviviruses dengue (DEN) and West Nile (WN), and alphavirus Chikungunya (CHIK). The knowledge of such mechanisms will yield crucial informations to guide diagnosis, prophylaxis and therapy of arbovirus-related diseases.

National Reference Center for Arboviruses. The National Reference Center (NRC) for Arboviruses became part of the laboratory from May 2008. The NRC has the general mission of epidemiologic alarm, the expertise in the arboviral diagnosis and the investigation of the epidemics of arboviroses with the provision of logistics at the time including in the exposed zones.

Cellular interactors to flavivirus proteins. We have identified a cellular protein (Tctex-1) that interacts with the M membrane protein of flaviviruses, using the yeast two-hybrid technology. We are currently investigating the role of this interaction in the flaviviral life cycle and pathogenicity. Cellular interactors to non-structural proteins from neurotropic flaviviruses have also been identified, and we are now in the process of establishing a physiological role for these interactions (in collaboration with P.O. Vidalain and V. Deubel).

Innate immunity to flaviviruses. Human dermal DCs and dermal macrophages carry the C-type lectin DC-SIGN (CD209). This molecule plays an essential role as attachment receptor for productive infection of human DCs by DEN virus. Although dermal macrophages were able to internalize DEN virions, these cells are refractory for productive virus infection. The inability of DEN virus to grow in dermal macrophages was attributable to accumulation of internalized virus particles into poorly-acidified phagosomes (coll. C. Mueller). Members of interferon-inducible 2’,5’-Oligoadenylate Synthetase (OAS) family play a role in innate immunity to flaviviruses. The 1b isoform of mouse OAS gene is a critical component of innate immunity to WN virus in vivo and in vitro. To explore the molecular basis of antiviral effect of Oas1b against WN virus, escape virus variants to Oas1b were generated. We investigate the impact of identified mutations on the sensitivity of WN virus to antiviral effect of Oas1b.

Pathogenicity of Chikungunya virus. Characterization of infection dynamics of CHIK virus in muscle cells and epithelial cells is important since both cell types may play an essential role in pathogenesis of disease in humans (in collaboration with A-B. Failloux, S. Ozden, T. Couderc, and M. Lecuit). In infected human epithelial cells, CHIK virus is highly sensitive to antiviral activity of the large form of human OAS (OAS3). The genetic polymorphism of OAS3 alters its antialphaviral activity suggesting a role for OAS3 in the severity of CHIKV-related disease (in collaboration with A. Sakuntabhai).

Dengue vaccine. Dengue disease is an increasing global health problem. With the aim to propose an affordable vaccine that could be used in young populations living in tropical countries, we pursue the evaluation of a candidate dengue vaccine based on tetravalent dengue antigen inserted into a vector derived from the live-attenuated pediatric Schwarz measles measles vaccine (in collaboration with H. Bedouelle and F. Tangy).

Keywords: arbovirus, flavivirus, alphavirus, dengue, West Nile, Chikungunya, viral pathogenicity, innate immunity, vaccine

Imfh.jpg

Dengue envelope protein (green) endocytosed into myeloid dendritic cell

(Wang et al., PloS NTD 2:e311, 2008)



  Publications

Bréhin, A-C., Casadémont, I., Frenkiel, M-P., Julier, C., Sakuntabhai, A., and Desprès, P. (2008). The large form of human 2',5'-Oligoadenylate Synthetase (OAS3) exerts antiviral activity against Chikungunya virus.Virology doi :10.1016/j.virol.2008.10.021

Wing, W-H., Navarro-Sanchez, E., Dumortier, H., Decossas, M., Barreto dos Santos, F., Fridman, H.W., Rey, F., Harris, E., Desprès, P., and Mueller, C.G. (2008). Dermal-type macrophages expressing CD209/DC-SIGN show inherent resistance to dengue virus growth.PLoS Negl. Trop. Dis.2(10) :e311.

Brandler, S., Lucas-Hourani, M., Moris, A., Frenkiel, M-P., Combredet, C., Février, C., Bedouelle, H., Schwartz, O., Desprès, P., and Tangy, F. (2007). Pediatric measles vaccines expressing a dengue antigen induces durable serotype-specific neutralizing antibodies to dengue virus.PLoS Negl. Trop. Dis.1(3):e96.

Kajaste-Rudnitski, A., Mashimo, T., Frenkiel, M-P., Guénet, J.-L., Lucas, M., and Desprès , P. (2006). The 2'-5' Oligoadenylate Synthetase 1b is a potent inhibitor of West Nile replication inside infected cells.J.Biol.Chem. 281 : 4624-37.

Sakuntabhai, A., Turbpaiboo, C., Casadémont, I., Lowhnoo, A., Chuansumrit, T., Kajaste-Rudnitski, A., Kalayanarooj, S.M., Tangnararatchakit, K., Tangthawornchaiku, N., Vasanawathana, S., Chaiyaratana, W., Yenchitsomanus, P., Suriyaphol, P., Avirutnan, P., Chokephaibulkit, K., Matsuda, F., Yoksan, S., Jacob, Y., Lathrop, M., Malasit, P., Desprès, P., and Julier, C. (2005). A variant in the CD209 promoter is associated with the severity of dengue disease.Nat. Genet. 37:507-13





Activity Reports 2009 - Institut Pasteur
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